Crystalline Solid Forms of N-{4-[(6,7-Dimethoxyquinolin-4-yl)oxy]phenyl}-N&#39;-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, Processes for Making, and Methods of Use

ABSTRACT

The invention relates to novel crystalline solid forms of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1), and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib.

PRIORITY CLAIM

This application is a divisional of U.S. application Ser. No.15/118,738, filed Aug. 12, 2016, which is a 371 of InternationalApplication Serial No. PCT/US2015/016052, filed Feb. 16, 2015, whichclaims the benefit of U.S. Provisional Application Ser. No. 61/939,985,filed Feb. 14, 2014, all of which are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

The invention relates to novel crystalline solid forms of the chemicalcompoundN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and solvates thereof, includinghydrates, that are useful for the treatment of cancer. Also disclosedare pharmaceutical compositions comprising the crystalline solid formsand processes for making the crystalline solid forms, as well as methodsof using them for the treatment of cancer, particularly thyroid cancer,prostate cancer, hepatocellular cancer, renal cancer, and non-small celllung carcinoma.

BACKGROUND OF THE INVENTION

Commonly assigned PCT Patent Publication No. WO 2005/030140,incorporated by reference herein in its entirety, discloses novelinhibitors of multiple receptor tyrosine kinases (RTKs) implicated intumor growth and angiogenesis, pathologic bone remodeling, andmetastatic progression of cancer. In particular, the compoundN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is specifically described in WO2005/030140 as an RTK inhibitor. The chemical structure ofN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is represented by Compound 1.

Compound 1 was found to have an enzyme Ret IC₅₀ value of about 5.2 nM(dihydrate) and an enzyme c-Met IC₅₀ value of about 1.3 nM (dihydrate).The assay that was used to measure this c-Met activity is described inparagraph [0458] in WO2005/030140.

During initial development experiments, Compound 1 (a free base) wasfound to be a BCS class II compound having low solubility and highpermeability. Because Compound 1 was observed to have low solubility inwater, it was initially considered unsuitable for solid oral dosagedevelopment, and hence the pharmaceutical development focused on findinga salt with suitable hygroscopicity, thermal stability, chemicalstability, physical stability, and solubility.

The malate salt of the Compound 1, as described in WO 2010/083414, theentire contents of which is incorporated by reference, was subsequentlyidentified as providing an acceptable combination of crystallinity,solubility, and stability as compared to cabozantinib free base. On Nov.29, 2012, the S-malate salt ofN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (also known as cabozantinib or COMETRIQ®)was approved by the United States Food and Drug Administration for thetreatment of progressive, metastatic medullary thyroid cancer (MTC). InDecember 2013, the European Committee for Medicinal Products for HumanUse (CHMP), issued a positive opinion on the Marketing AuthorizationApplication (MAA), submitted to the European Medicines Agency, or EMA,for COMETRIQ for the proposed indication of progressive, unresectable,locally advanced, or metastatic MTC. Cabozantinib is being evaluated ina broad development program, including ongoing phase 3 pivotal trials inmetastatic renal cell cancer (RCC), and advanced hepatocellular cancer(HCC).

Besides therapeutic efficacy, the Applicant continues to endeavor toprovide suitable form(s) of Compound 1 that have favorable propertiesrelated to processing, manufacturing, storage stability, and/orusefulness as a drug. Accordingly, the discovery of new crystallinesolid forms of Compound 1 that possesses some or all of these desiredproperties remains vital to drug development. Thus, disclosed herein arenovel crystalline solid forms of Compound 1 that may be used inpharmaceutical compositions for the treatment of proliferative diseasessuch as cancer.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention, which isdirected to novel crystalline solid forms of Compound 1, as well aspharmaceutical compositions containing, methods for using, and processesfor making such crystalline solid forms. The crystalline solid formsinclude free base crystalline solid forms, as well as solvate, includinghydrate, crystalline solid forms. Among other uses, crystalline solidforms of Compound 1 are useful for preparing pharmaceutical compositionsexpected to have utility in treating cancer. Accordingly, one aspect ofthe invention pertains to a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a solid form of Compound 1.

As indicated previously, Compound 1 inhibits multiple receptor tyrosinekinases (RTKs) implicated in tumor growth and angiogenesis, pathologicbone remodeling, and metastatic progression of cancer. Accordingly,crystalline solid forms of the Compound 1 are useful for treatingcancer. Thus, another aspect of the invention pertains to a method fortreating cancer comprising administering to a subject a therapeuticallyeffective amount of a solid form of Compound 1 as disclosed herein. Theinvention is also directed to processes for preparing crystalline solidforms of Compound 1.

As a further aspect, any of the crystalline solid forms disclosed hereincan be used to make pharmaceutically acceptable salts ofN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, including its S-malate salt, which issold as cabozantinib.

BRIEF DESCRIPTION THE DRAWINGS

Various aspects of the present invention are illustrated by reference tothe following drawings.

FIG. 1 shows the experimental x-ray powder diffraction (XRPD) pattern ofamorphous Compound 1 prepared by lyophilisation.

FIG. 2 shows the experimental x-ray powder diffraction (XRPD) patternfor Compound 1 Form I.

FIG. 3 shows the thermogravimetric differential thermal analysis(TG/DTA) thermogram for Compound 1 Form I, run from 30-300° C. at 10°C./min.

FIG. 4 shows the differential scanning calorimetry (DSC) thermogram forCompound 1 Form I, run from 30-300° C. at 10° C./min.

FIG. 5 shows the Fourier transfer infrared (FT-IR) spectrum for Compound1 Form I.

FIG. 6 shows the ¹H nuclear magnetic resonance (NMR) spectrum forCompound 1 Form I.

FIG. 7 shows the experimental x-ray powder diffraction (XRPD) patternfor Compound 1 Form II.

FIG. 8 shows the thermogravimetric differential thermal analysis(TG/DTA) thermogram for crystalline Compound 1 Form II, run from 30-300°C. at 10° C./min.

FIG. 9 shows the differential scanning calorimetry (DSC) thermogram forCompound 1 Form II, run from 30-300° C. at 10° C./min.

FIG. 10 shows the ¹H nuclear magnetic resonance (NMR) spectrum forCompound 1 Form II.

FIG. 11 shows the experimental x-ray powder diffraction (XRPD) patternfor Compound 1 Form III.

FIG. 12 shows the thermogravimetric differential thermal analysis(TG/DTA) thermogram for Compound 1 Form III, run from 30-300° C. at 10°C./min.

FIG. 13 shows the differential scanning calorimetry (DSC) thermogram forCompound 1 Form III, run from 30-300° C. at 10° C./min.

FIG. 14 shows the Fourier transfer infrared (FT-IR) spectrum forCompound 1 Form III.

FIG. 15 shows the ¹H nuclear magnetic resonance (NMR) spectrum forCompound 1 Form III.

FIG. 16 shows the experimental x-ray powder diffraction (XRPD) patternfor Compound 1 Form XXVIII.

FIG. 17 shows the thermogravimetric differential thermal analysis(TG/DTA) thermogram for Compound 1 Form XXVIII, run from 30-300° C. at10° C./min.

FIG. 18 shows the differential scanning calorimetry (DSC) thermogram forCompound 1 Form XXVIII, run from 30-300° C. at 10° C./min.

FIG. 19 shows the Fourier transfer infrared (FT-IR) spectrum forCompound 1 Form XXVIII.

FIG. 20 shows the ¹H nuclear magnetic resonance (NMR) spectrum forCompound 1 Form XXVIII.

FIG. 21 shows the experimental x-ray powder diffraction (XRPD) patternfor Compound 1 Form XXX.

FIG. 22 shows the thermogravimetric differential thermal analysis(TG/DTA) thermogram for Compound 1 Form XXX, run from 30-300° C. at 10°C./min.

FIG. 23 shows the differential scanning calorimetry (DSC) thermogram forCompound 1 Form XXX, run from 30-300° C. at 10° C./min.

FIG. 24 shows the Fourier transfer infrared (FT-IR) spectrum forCompound 1 Form XXX.

FIG. 25 shows the ¹H nuclear magnetic resonance (NMR) spectrum forCompound 1 Form XXX.

FIG. 26 shows the experimental x-ray powder diffraction (XRPD) patternfor Compound 1 Form XXXI.

FIG. 27 shows the thermogravimetric differential thermal analysis(TG/DTA) thermogram for Compound 1 Form XXXI, run from 30-300° C. at 10°C./min

FIG. 28 shows the differential scanning calorimetry (DSC) thermogram forCompound 1 Form XXXI, run from 30-300° C. at 10° C./min.

FIG. 29 shows the Fourier transfer infrared (FT-IR) spectrum forCompound XXXI, Form I.

FIG. 30 shows the ¹H nuclear magnetic resonance (NMR) spectrum forCompound 1 Form XXXI.

DETAILED DESCRIPTION OF THE INVENTION Definitions

When describing the compounds, compositions, methods, and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, i.e., a crystalline Compound 1, and one or moremolecules of a solvent. Such solvates typically have a substantiallyfixed molar ratio of solute and solvent. This term also includesclathrates, including clathrates with water. Representative solventsinclude, for example, water, methanol, ethanol, isopropanol, aceticacid, and the like. When the solvent is water, the solvate formed is ahydrate.

“Therapeutically effective amount” means an amount sufficient to effecttreatment when administered to a subject in need of treatment. Forexample, a therapeutically effective amount for, as described below.“The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the disease state and its severity, the age of the subject to betreated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art taking intoconsideration his own knowledge and to this disclosure. Thus, a“therapeutically effective amount” of Compound 1 refers to an amountsufficient to treat a subject suffering from any of a variety of cancersassociated with abnormal cell proliferation and angiogenesis. Atherapeutically effective amount according to this disclosure is anamount therapeutically useful for the treatment or prevention of thedisease states and disorders discussed herein. Compound 1 (including thesolid state forms disclosed herein) possess therapeutic activity toinhibit, regulate, and/or modulate the signal transduction of kinasessuch as described in WO2005-030140.

“Treating” or “treatment” as used herein means the treatment of adisease-state in a human, which disease-state is characterized byabnormal cellular proliferation, and invasion and includes at least oneof: (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it; (ii) inhibiting the disease-state,i.e., arresting its development; and (iii) relieving the disease-state,i.e., causing regression of the disease-state.

The term “pharmaceutically acceptable” refers to a material that is notbiologically or otherwise undesirable. For example, the term“pharmaceutically acceptable carrier” refers to a material that can beincorporated into a composition and administered to a subject withoutcausing undesirable biological effects or interacting in a deleteriousmanner with other components of the composition. Such pharmaceuticallyacceptable materials typically have met the required standards oftoxicological and manufacturing testing and include those materialsidentified as suitable inactive ingredients by the U.S. Food and DrugAdministration.

The term “dosage form” refers to a physically discrete unit suitable fordosing a subject, i.e., each unit containing a predetermined quantity ofa compound of the invention calculated to produce the desiredtherapeutic effect either alone or in combination with one or moreadditional units. For example, such unit dosage forms may be capsules,tablets, pills, and the like.

As used herein, “amorphous” refers to a solid form of a molecule and/orion that is not crystalline. An amorphous solid does not display adefinitive X-ray diffraction pattern with sharp maxima.

As used herein, the term “substantially pure” means the solid form ofCompound 1 referred to contains at least about 90 weight percent basedon the weight of such solid form. The term “at least about 90 weightpercent,” while not intending to limit the applicability of the doctrineof equivalents to the scope of the claims, includes, but is not limitedto, for example, about 90, about 91, about 92, about 93, about 94, about95, about 96, about 97, about 98, about 99, and about 100 weightpercent, based on the weight of the solid form referred to. Theremainder of the solid form of Compound 1 may comprise other solidform(s) of Compound 1 and/or reaction impurities and/or processingimpurities that arise, for example, when the crystalline form isprepared. The presence of reaction impurities and/or processingimpurities may be determined by analytical techniques known in the art,such as, for example, chromatography, nuclear magnetic resonancespectroscopy, mass spectroscopy, and/or infrared spectroscopy.

Embodiments

This disclosure relates to solid solvate forms of Compound 1, as well asunsolvated (otherwise known as “anhydrous” or “free base”) crystallinesolid forms of Compound 1. The forms disclosed herein each representseparate aspects of the disclosure. Although the crystalline solid formsare described herein, the invention also relates to novel compositionscontaining the disclosed crystalline solid forms. Therapeutic uses ofthe crystalline solid forms described as well as therapeuticcompositions containing them represent separate aspects of thedisclosure. The techniques used to characterize the crystalline solidforms are described in the examples below. These techniques, alone or incombination, may be used to characterize the crystalline forms disclosedherein. The crystalline solid forms may be also characterized byreference to the disclosed figures.

Crystalline Solid Forms of Compound 1

This disclosure relates to crystalline solid forms of Compound 1. Thecrystalline solid forms include:

-   -   A crystalline dihydrate form of Compound designated as Compound        1 Form I;    -   A crystalline solvate form of Compound designated as Compound 1        Form II;    -   A crystalline anhydrous (“free base”) form of Compound 1        designated as Compound 1 Form III;    -   A crystalline anhydrous (“free base”) form of Compound 1        designated as Compound 1 Form XXVIII;    -   A crystalline anhydrous (“free base”) form of Compound 1        designated as Compound 1 Form XXX; and    -   A crystalline dihydrate form of Compound 1 designated as        Compound 1 Form XXXI.

The names used herein to characterize a specific form, e.g. “Form I,”etc., are not to be limited so as to exclude any other substancepossessing similar or identical physical and chemical characteristics,but rather such names are used as mere identifiers that are to beinterpreted in accordance with the characterization informationpresented herein.

Each form of Compound 1 is a separate aspect of the disclosure. Mixturesof the crystalline solid forms of Compound 1 are another aspect of thedisclosure. Compound 1 Forms have various desirable properties fordevelopment.

Compound 1 Form I may be characterized by at least one of the following:

-   -   (i) an x-ray powder diffraction pattern (CuKα) comprising two or        more peaks as depicted in FIG. 2, wherein measurement of the        crystalline form is at an ambient room temperature; and    -   (ii) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 2.

Compound 1 Form I may be characterized by an x-ray powder diffractionpattern (CuKα) comprising peaks at 10.1, 11.9, 12.9, 14.4, 16.0, 23.0,23.6, and 24.7 (° 2θ+0.2°2θ). In another embodiment, Compound 1 Form Imay be characterized by an x-ray powder diffraction pattern (CuKα)comprising peaks at 10.1, 11.9, 12.9, 14.4, 16.0, and 23.6 (°2θ+0.2°2θ). In another embodiment, Compound 1 Form I may becharacterized by an x-ray powder diffraction pattern (CuKα) comprisingpeaks at 10.1 and 12.9 (° 2θ+0.2°2θ). In a further embodiment, Compound1 Form I may be characterized by an x-ray powder diffraction pattern(CuKα) comprising peaks at 11.9, 14.4, 16.0, and 23.6 (° 2θ+0.2°2θ).

Other solid state properties which may be used to characterize Compound1 Form I are shown in the FIGS. (FIGS. 3-6) and discussed in theexamples below. For example, thermogravimetric/differential analysis(TG/DTA) of Compound 1 Form I showed weight loss of 6.5 percent, from25-80° C., corresponding to the loss of 1.92 moles of water, indicatingthat Compound 1 Form I is a dihydrate (FIG. 3). The hygroscopicity andthe sorption properties of Compound 1 Form I indicated very small weightgain between 40% RH and 90% RH, indicating that Compound 1 Form I isstable and non-hygroscopic at higher humidity.

Compound 1 Form I can be prepared by agitating a mixture of Compound 1Form I or amorphous Compound 1 and THF at ambient temperature until theCompound 1 is dissolved. Water is then added portionwise, and themixture is stirred for a sufficient time. The solid Compound 1 Form I iscollected and dried.

Compound 1 Form II may be characterized by at least one of thefollowing:

-   -   (i) an x-ray powder diffraction pattern (CuK α) comprising two        or more peaks as depicted in FIG. 7, wherein measurement of the        crystalline form is at an ambient room temperature; and    -   (ii) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 7.

In on embodiment, Compound 1 Form II may be characterized by an x-raypowder diffraction pattern (CuKα) comprising peaks at 6.4, 11.6, 12.1,12.6, 12.9, 14.8, 14.9, 18.0, 18.8, and 20.2 (° 2θ+0.2°2θ). In anotherembodiment, Compound 1 Form II may be characterized by an x-ray powderdiffraction pattern (CuKα) comprising peaks at 6.4, 11.6, 12.1, 12.6,12.9, 14.8, 14.9, and 20.2 (° 2θ+0.2°2θ). In another embodiment,Compound 1 Form II may be characterized by an x-ray powder diffractionpattern (CuKα) comprising peaks at 11.6, 12.1, 12.6, 12.9, and 14.9 (°2θ+0.2°2θ). In a further embodiment, Compound 1 Form II may becharacterized by an x-ray powder diffraction pattern (CuKα) comprisingpeaks at 6.4, 8.6, 14.9, and 20.2 (° 2θ+0.2°2θ).

Other solid state properties which may be used to characterize Compound1 Form II are shown in the FIGS. (FIGS. 8-10) and discussed in theexamples below. For example, thermogravimetric/differential analysis(TG/DTA) of Compound 1 Form II showed weight loss of 9.8 percent,attributable to the loss of a mixture of tetrahydrofuran (THF) and water(FIG. 8).

Compound 1 Form II can be prepared by agitating a mixture of Compound 1Form I and THF at ambient temperature until the Compound 1 Form I isdissolved. Water is then added portionwise, and the mixture is stirredfor a sufficient time. The solid Compound 1 Form II is collected anddried.

Compound 1 Form III may be characterized by at least one of thefollowing:

-   -   (i) an x-ray powder diffraction pattern (CuKα) comprising two or        more peaks as depicted in FIG. 11, wherein measurement of the        crystalline form is at an ambient room temperature; and    -   (ii) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 11.

In one embodiment, Compound 1 Form III may be characterized by an x-raypowder diffraction pattern (CuKα) comprising peaks at 7.0, 7.8, 9.4,11.1, 12.6, 14.1, 15.5, 17.3 22.3, and 24.3 (° 2θ+0.2°2θ). In anotherembodiment, Compound 1 Form III may be characterized by an x-ray powderdiffraction pattern (CuKα) comprising peaks at 7.0, 7.8, 9.4, 11.1,12.6, 14.1, 22.3, and 24.3 (° 2θ+0.2°2θ). In another embodiment,Compound 1 Form III may be characterized by an x-ray powder diffractionpattern (CuKα) comprising peaks at 9.4, 12.6, 22.3, and 24.3 (°2θ+0.2°2θ). In a further embodiment, Compound 1 Form III may becharacterized by an x-ray powder diffraction pattern (CuKα) comprisingpeaks at 7.0, 7.8, 11.1, and 14.1 (° 2θ+0.2°2θ).

Other solid state properties which may be used to characterize Compound1 Form III are shown in the FIGS. (FIGS. 12-15) and discussed in theexamples below. For example, no weight loss was observed in the TG/DTAanalysis of Compound 1 Form III, indicating that Compound 1 Form III isan anhydrous material (FIG. 12). The hygroscopicity and the sorptionproperties of Compound 1 Form III indicated very small weight gainbetween 0% RH and 80% RH, indicating that Compound 1 Form III isnon-hygroscopic according to the European Pharmacopeia classification.

Compound 1 Form III can be prepared by agitating a mixture of Compound 1Form I and THF at ambient temperature until Compound 1 Form I isdissolved. The mixture is then heated to a temperature of at least 40°C. and the pressure is reduced to approximately 100 torr. Afterapproximately one-half of the volume of THF was removed by distillation,methanol was added to the flask to achieve the approximate startingvolume. This distillation was repeated at least two times, and themixture was returned to ambient temperature and pressure. The resultingsolids were collected and dried.

Compound 1 Form XXVIII may be characterized by at least one of thefollowing:

-   -   (i) an x-ray powder diffraction pattern (CuKα) comprising two or        more peaks as depicted in FIG. 16, wherein measurement of the        crystalline form is at an ambient room temperature; and    -   (ii) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 16.

In one embodiment, Compound 1 Form XXVIII may be characterized by anx-ray powder diffraction pattern (CuKα) comprising peaks at 6.5, 9.5,11.8, 12.3, 13.04, 15.5, 16.9, 17.7, 19.1, 21.7 and 22.3 (° 2θ+0.2°2θ).In another embodiment, Compound 1 Form XXVIII may be characterized by anx-ray powder diffraction pattern (CuKα) comprising peaks at 6.5, 9.5,11.8, 12.3, 13.0, 17.7, 19.1, and 22.3 (° 2θ±0.2°2θ). In anotherembodiment, Compound 1 Form XXVIII may be characterized by an x-raypowder diffraction pattern (CuKα) comprising peaks at 9.5, 11.8, 13.0,and 22.3 (° 2θ+0.2°2θ). In a further embodiment, Compound 1 Form XXVIIImay be characterized by an x-ray powder diffraction pattern (CuKα)comprising peaks at 6.5, 12.3, 17.7, 19.1 (° 2θ+0.2°2θ).

Other solid state properties which may be used to characterize Compound1 Form XXVIII are shown in the FIGS. (FIGS. 17-20) and discussed in theexamples below. For example, no weight loss was observed in the TG/DTAanalysis of Compound 1 Form XXVIII, indicating that Compound 1 FormXXVIII is an anhydrous material (FIG. 17). The hygroscopicity and thesorption properties indicated very small weight gain between 0% RH and80% RH, indicating that Compound 1 Form XXVIII is non-hygroscopic.

Compound 1 Form XXVIII can be prepared by combining Compound 1 Form Iand 1-butanol at low temperature (e.g., 0-10° C.) for several days. Thesolid Compound 1 Form XXVIII was recovered by filtration and air dried.In an alternative procedure, amorphous Compound 1 can be slurried innitromethane for several days at room temperature. The resulting solidCompound 1 Form XXVIII are then collected, dried, and desolvated on aTG/DTA at 110° C. for 15 minutes.

Compound 1 Form XXX may be characterized by at least one of thefollowing:

-   -   (i) an x-ray powder diffraction pattern (CuKα) comprising two or        more peaks as depicted in FIG. 21, wherein measurement of the        crystalline form is at an ambient room temperature; and    -   (ii) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 21.

In one embodiment, Compound 1 Form XXX may be characterized by an x-raypowder diffraction pattern (CuKα) comprising peaks at 7.2, 7.5, 10.0,12.0, 12.4, 13.5, 15.8, and 19.8 (° 2θ+0.2°2θ). In another embodiment,Compound 1 Form XXX may be characterized by an x-ray powder diffractionpattern (CuKα) comprising peaks at 7.2, 7.5, 10.0, 12.0, 12.4, 13.5, and19.8 (° 2θ+0.2°2θ). In another embodiment, Compound 1 Form XXX may becharacterized by an x-ray powder diffraction pattern (CuKα) comprisingpeaks at 10.0, 12.0, and 12.4 (° 2θ+0.2°2θ). In a further embodiment,Compound 1 Form XXX may be characterized by an x-ray powder diffractionpattern (CuKα) comprising peaks at 7.2, 7.5, 13.5, and 19.8 (°2θ+0.2°2θ).

Other solid state properties which may be used to characterize Compound1 Form XXX are shown in the FIGS. (FIGS. 21-25) and discussed in theexamples below. For example, no weight loss was observed in the TG/DTAanalysis of Compound 1 Form XXX, indicating that Compound 1 Form XXX isan anhydrous material (FIG. 22). The hygroscopicity and the sorptionproperties of Compound 1 Form XXX indicated that Compound 1 Form XXX ishygroscopic according to the European Pharmacopeia classification.

Compound 1 Form XXX can be prepared by adding amorphous Compound 1 to acontainer. The container is placed unsealed inside a larger containerthat contains acetone. After several days, the material can bedesolvated on a TG/DTA at 105° C. for 25 minutes followed by desolvationat 100° C. for 40 minutes to yield Compound 1 Form XXX.

Compound 1 Form XXXI may be characterized by at least one of thefollowing:

-   -   (i) an x-ray powder diffraction pattern (CuKα) comprising two or        more peaks as depicted in FIG. 26, wherein measurement of the        crystalline form is at an ambient room temperature; and    -   (ii) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 26.

In one embodiment, Compound 1 Form XXXI may be characterized by an x-raypowder diffraction pattern (CuKα) comprising peaks at 5.0, 10.0, 11.9,13.0, 14.4, 16.1, 19.9, 21.4, and 23.8 (° 2θ+0.2°2θ). In anotherembodiment, Compound 1 Form XXXI may be characterized by an x-ray powderdiffraction pattern (CuKα) comprising peaks at 5.0, 10.0, 11.9, and 13.0(° 2θ+0.2°2θ). In a further embodiment, Compound 1 Form XXXI may becharacterized by an x-ray powder diffraction pattern (CuKα) comprisingpeaks at 14.4, 16.1, 19.9, and 23.8 (° 2θ+0.2°2θ).

Other solid state properties which may be used to characterize Compound1 Form XXXI are shown in the FIGS. (FIGS. 27-30) and discussed in theexamples below. For example, 6.61 percent weight loss was observed inthe TG/DTA analysis of Compound 1 Form XXXI, indicating that Compound 1Form XXXI is a dihydrate (FIG. 27).

Compound 1 Form XXXI can be prepared by stirring a mixture of Compound 1Form III in 2-methyltetrahydrofuran at 0-10° C. for at least two weeksto allow for saturation. Compound 1 Form I and Compound 1 Form XXXI wereadded, and the mixture was stirred for several days to allow forcomplete conversion to Compound 1 Form XXXI. The solid was recovered byvacuum filtration and dried on the filter.

In an embodiment, the disclosure relates to a solid form of Compound 1,as described herein in any of the aspects and/or embodiments, which issubstantially pure Compound 1 Form I.

In another embodiment, the disclosure relates to a solid form ofCompound 1, as described herein in any of the aspects and/orembodiments, which is substantially pure Compound 1 Form II.

In another embodiment, the disclosure relates to a solid form ofCompound 1, as described herein in any of the aspects and/orembodiments, which is substantially pure Compound 1 Form III.

In another embodiment, the disclosure relates to a solid form ofCompound 1, as described herein in any of the aspects and/orembodiments, which is substantially pure Compound 1 Form XXVIII.

In another embodiment, the disclosure relates to a solid form ofCompound 1, as described herein in any of the aspects and/orembodiments, which is substantially pure Compound 1 Form XXX.

In another embodiment, the disclosure relates to a solid form ofCompound 1, as described herein in any of the aspects and/orembodiments, which is substantially pure Compound 1 Form XXXI.

A further aspect of the disclosure relates to mixtures of thecrystalline solid forms of Compound 1 as described herein in any of theaspects and/or embodiments.

Each of the crystalline solid forms of Compound 1 described herein hasunique characteristics that can distinguish them one from another. Thesecharacteristics can be understood by comparing the physical propertiesof the solid state forms which are presented in the Examples below.

In another embodiment, the invention is directed to Compound 1crystalline solid Form I, II, III, XXVIII, XXX, or XXXI with an XRPDpattern selected from the group consisting of:

Compound 1 Form Form Form Form Form Form I II III XXVIII XXX XXXI 10.16.4 7.0 6.5 7.2 5.0 11.9 11.6 7.8 9.5 7.5 10.0 12.9 12.1 9.4 11.8 10.011.9 14.4 12.6 11.1 12.3 12.0 13.0 16.0 12.9 12.6 13.0 12.4 14.4 23.014.8 14.1 15.5 13.5 16.1 23.6 14.9 15.5 16.9 15.8 19.9 24.7 18.0 17.317.7 19.8 21.4 18.8 22.3 19.1 23.8 20.2 24.3 21.7 22.3

In another embodiment, the invention is directed to Compound 1crystalline solid Form I, II, II, XXVIII, XXX, or XXXI with an XRPDpattern selected from the group consisting of:

Compound 1 Form Form Form Form Form Form I II III XXVIII XXX XXXI 10.16.4 7.0 6.5 7.2 5.0 11.9 8.6 7.8 9.5 7.5 10.0 12.9 12.1 9.4 11.8 10.011.9 14.4 12.6 11.1 12.3 12.0 13.0 16.0 12.9 12.6 13.0 12.4 14.3 23.614.8 14.1 17.7 13.5 14.4 14.9 22.3 19.1 19.8 16.1 20.2 24.3 22.3 19.923.8

In another embodiment, the invention is directed to Compound 1crystalline solid Form I, II, III, XXVIII, XXX, or XXXI with an XRPDpattern selected from the group consisting of:

Compound 1 Form Form Form Form Form Form I II III XXVIII XXX XXXI 11.96.4 7.0 6.5 7.2 14.4 14.4 8.6 7.8 12.3 7.5 16.1 16.0 14.9 11.1 17.7 13.519.9 23.6 20.2 14.1 19.1 19.8 23.8

In another embodiment, the invention is directed to Compound 1crystalline solid Form I, II, III, XXVIII, XXX, or XXXI with an XRPDpattern selected from the group consisting of:

Compound 1 Form Form Form Form Form Form I II III XXVIII XXX XXXI 10.111.6 9.4 9.5 10.0 5.0 12.9 12.1 11.5 11.8 12.0 10.0 12.6 12.6 13.0 12.411.9 12.9 22.3 22.3 13.0 14.9 24.3 14.3

In another embodiment, the the invention is directed to a crystallinesolid form of compound 1 of claims 1-5 having an XRPD patterns asrepresented by:

Compound 1 Form I Form III Form XXVIII Form XXX Form XXXI FIG. 2 FIG. 11FIG. 16 FIG. 21 FIG. 26

As indicated above the disclosed herein can be used to form the L-malatesalt of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinolone-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (cabozantinib). For example, L-malic acid can beadded to a solution of, cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinolone-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide free base in ethanol, maintaining a temperatureof approximately 25° C. Carbon (0.5 kg) and thiol silica (0.1 kg) arethen added, and the resulting mixture is heated to approximately 78° C.,at which point water (6.0 kg) is added. The reaction mixture is thenfiltered, followed by the addition of isopropanol (38.0 kg), and isallowed to cool to approximately 25° C. The product is recovered byfiltration and washed with isopropanol (20.0 kg) and dried atapproximately 65° C. to afford the L-malate salt ofcyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinolone-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide.

Pharmaceutical Compositions and Methods of Treatment

Another aspect of this disclosure relates to a pharmaceuticalcomposition comprising at least one crystalline solid form of Compound 1as described herein in any of the aspects and/or embodiments, orcombinations thereof, and a pharmaceutically acceptable excipient.Pharmaceutical compositions of Compound 1 have been disclosed in, forexample, commonly assigned PCT Patent Publication Nos. WO 2005/030140,WO 2012/009722, and WO 2012/109510, each of which is incorporated byreference herein in its entirety.

The amount of the crystalline Compound 1 solid form or combinationsthereof in the pharmaceutical composition can be a therapeuticallyeffective amount. The crystalline solid forms of Compound 1 mayindividually be present in the pharmaceutical composition or ascombinations. The crystalline solid forms as disclosed herein includeCompound 1 Form I, Compound 1 Form II, Compound 1 Form III, Compound 1Form XXVIII, Compound 1 Form XXX, and Compound 1 Form XXXI. Accordingly,another aspect of this disclosure relates to a solid or dispersionpharmaceutical composition comprising at least one of a therapeuticallyeffective amount of a solid form of Compound 1, as described herein inany of the aspects and/or embodiments, or combinations thereof, and apharmaceutically acceptable excipient.

A pharmaceutical composition such as disclosed herein may be anypharmaceutical form which contains an active crystalline Compound 1solid form. The pharmaceutical composition may be, for example, atablet, capsule, liquid suspension, injectable, topical, or transdermal.The pharmaceutical compositions generally contain about 1% to about 99%by weight of the active compound(s), or a solid form of the activecompound(s), and 99% to 1% by weight of a suitable pharmaceuticalexcipient. In one example, the composition will be between about 5% andabout 75% by weight of active compound, with the rest being suitablepharmaceutical excipients or other adjuvants, as discussed below.

The actual amount required for treatment of any particular subject willdepend upon a variety of factors including the disease state beingtreated and its severity; the specific pharmaceutical compositionemployed; the age, body weight, general health, sex, and diet of thesubject; the mode of administration; the time of administration; theroute of administration; and the rate of excretion of the activecompound(s), or a solid form of the active compound(s), according tothis disclosure; the duration of the treatment; any drugs used incombination or coincidental with the specific compound employed; andother such factors well known in the medical arts. These factors arediscussed in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics,” Tenth Edition, A. Gilman, J. Hardman and L. Limbird,eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein byreference. The active compound(s), or a solid form of activecompound(s), according to this disclosure and pharmaceuticalcompositions comprising them, may be used in combination with anticanceror other agents that are generally administered to a subject beingtreated for cancer. They may also be co-formulated with one or more ofsuch agents in a single pharmaceutical composition.

Depending on the type of pharmaceutical composition, thepharmaceutically acceptable carrier may be chosen from any one or acombination of carriers known in the art. The choice of thepharmaceutically acceptable carrier depends partly upon the desiredmethod of administration to be used. For a pharmaceutical composition ofthis disclosure, that is, one of the active compound(s), or a solid formof the active compound(s), of this disclosure, a carrier should bechosen so as to substantially maintain the particular form of the activecompound(s), whether it would be solid or not. In other words, thecarrier should not substantially alter the form of the activecompound(s). Nor should the carrier be otherwise incompatible with theform of the active compound(s), such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutical composition.

The pharmaceutical compositions of this disclosure may be prepared bymethods know in the pharmaceutical formulation art, for example, seeRemington's Pharmaceutical Sciences, 18^(th) Ed., (Mack PublishingCompany, Easton, Pa., 1990). In solid dosage forms, Compound 1 Form I,II, III, XXVIII, or XXX, or combinations thereof, is admixed with atleast one pharmaceutically acceptable excipient such as sodium citrateor dicalcium phosphate or (a) fillers or extenders, as for example,starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b)binders, as for example, cellulose derivatives, starch, alginates,gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants,as for example, glycerol, (d) disintegrating agents, as for example,agar-agar, calcium carbonate, potato or tapioca starch, alginic acid,croscarmellose sodium, complex silicates, and sodium carbonate, Isolution retarders, as for example paraffin, (f) absorptionaccelerators, as for example, quaternary ammonium compounds, (g) wettingagents, as for example, cetyl alcohol, and glycerol monostearate,magnesium stearate, and the like (h) adsorbents, as for example, kaolinand bentonite, and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents.

Pharmaceutically acceptable adjuvants known in the pharmaceuticalformulation art may also be used in the pharmaceutical compositions ofthis disclosure. These include, but are not limited to, preserving,wetting, suspending, sweetening, flavoring, perfuming, emulsifying, anddispensing agents. Prevention of the action of microorganisms can beensured by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, and the like. It may alsobe desirable to include isotonic agents, for example sugars, sodiumchloride, and the like. If desired, a pharmaceutical composition of thisdisclosure may also contain minor amounts of auxiliary substances suchas wetting or emulsifying agents, pH buffering agents, and antioxidants,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, and butylated hydroxytoluene.

In some instances, the pharmaceutical dosage form may be a soliddispersion. The term “solid dispersion” refers to a system in a solidstate comprising at least two components, wherein one component isdispersed throughout the other component or components. For example, thecan be an amorphous solid dispersion. The term “amorphous soliddispersion” as used herein, refers to stable solid dispersionscomprising amorphous drug substance (Compound 1) and a stabilizingpolymer. By “amorphous drug substance,” it is meant that the amorphoussolid dispersion contains drug substance in a substantially amorphoussolid state form, that is at least 80% of the drug substance in thedispersion is in an amorphous form. More preferably, at least 90% andmost preferably at least 95% of the drug substance in the dispersion isin amorphous form. The term “stabilizing polymer” any polymer known tothe skilled practitioner that is used to stabilize an amorphous drugsubstance in a solid dispersion such as are described, for instance, inRemington's Pharmaceutical Sciences, 18^(th) Ed., (Mack PublishingCompany, Easton, Pa., 1990).

Processes for making such solid dispersions are also available to theskilled practitioner and include, for instance, spray drying, meltextrusion, freeze drying, rotary evaporation, drum drying, or othersolvent removal processes. In the spray drying process, the amorphousdispersion is formed by dispersing or dissolving the drug substance andthe stabilizing polymer in a suitable solvent to form a feed solution,pumping the feed solution through an atomizer into a drying chamber, andremoving the solvent to form the amorphous solid dispersion powder inthe drying chamber. A drying chamber uses hot gases, such as forced air,nitrogen, nitrogen-enriched air, or argon to dry particles. The feedsolution can be atomized by conventional means well known in the art,such as a two-fluid sonicating nozzle and a two-fluid non-sonicatingnozzle.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the active compound(s), or a solid formof the active compound(s), with, for example, suitable non-irritatingexcipients or carriers such as cocoa butter, polyethyleneglycol, or asuppository wax, which are solid at ordinary temperatures but liquid atbody temperature and therefore melt while in a suitable body cavity andrelease the active component therein.

Solid dosage forms are preferred for the pharmaceutical composition ofthis disclosure. Solid dosage forms for oral administration, whichincludes capsules, tablets, pills, powders, and granules, areparticularly preferred. In such solid dosage forms, the activecompound(s) mixed with at least one inert, pharmaceutically acceptableexcipient (also known as a pharmaceutically acceptable carrier).Administration of the active compound(s), or a solid form of the activecompound(s), in pure form or in an appropriate pharmaceuticalcomposition, can be carried out via any of the accepted modes ofadministration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages. One preferable route ofadministration is oral administration, using a convenient dosage regimenthat can be adjusted according to the degree of severity of thedisease-state to be treated.

Thus, in one embodiment, Compound 1 Form I, II, III, XXXVIII, XXX, orXXXI is administered as a pharmaceutical formulation additionallycomprising a pharmaceutically acceptable carrier and excipient. In someembodiments, the Compound 1 crystalline solid form is administered as atablet. In other embodiments, compound 1 is administered as a capsule.

In another embodiment, the invention is directed to a pharmaceuticaldosage form comprising 20 mg, 40 mg, 60 mg, 80 m6, 100 mg, 120 mg, or140 mg of Compound 1 Form I, II, III, XXXVIII, XXX, or XXXI or apharmaceutical composition comprising Compound 1 Form I, II, III,XXXVIII, XXX, or XXXI and a pharmaceutically acceptable carrier. Thedosage form can be administered orally with fasting once daily as atablet or capsule. In some embodiments, the dosage form is a tablet. Inother embodiments, the dosage form is a capsule.

The desired dosage of Compound 1 Form I, II, III, XXXVIII, XXX, or XXXIcan be achieved using a combination of tablets or capsules as needed.For example to achieve a target dose of 20 mg would requireadministration of one 20 mg tablet or capsule. To achieve a target doseof 100 mg would require administration of one 80 mg capsule or tabletand one 20 mg capsule or tablet. To achieve a target dose of 80 mg wouldrequire administration of one 80 mg capsule or tablet. To achieve atarget dose of 60 mg would require administration of three 20 mgcapsules or tablets.

For example, in one embodiment, 60 mg of Compound 1 Form I, II, III,XXXVIII, XXX, or XXXI is administered once daily to a patient withcancer in need of treatment. To achieve a dose of 60 mg of compound 1, apatient is administered three 20 mg tablets. The three 20 mg tablets canbe taken at the same time or sequentially. In a further embodiment,compound 1 is orally administered with fasting (that is, without eating)for approximately two hours before and 1 hour after administration.Compound 1 as one of the crystalline solid forms disclosed herein ispreferably administered with a glass of water (approximately 8ounces/240 mL).

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered once daily to a patient with cancer in needof treatment. To achieve a dose of 40 mg of compound 1, a patient isadministered two 20 mg tablets. The two 20 mg tablets can be taken atthe same time or sequentially. In a further embodiment, compound 1 isorally administered with fasting (that is, without eating) forapproximately two hours before and 1 hour after administration. Compound1 as one of the crystalline solid forms disclosed herein is preferablyadministered with a glass of water (approximately 8 ounces/240 mL).

In one embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII, XXX, orXXXI is administered once daily to a patient with cancer in need oftreatment. To achieve a dose of 20 mg of compound 1, a patient isadministered one 20 mg tablet. In a further embodiment, Compound 1 FormI, II, III, XXXVIII, XXX, or XXXI is orally administered with fasting(that is, without eating) for approximately two hours before and 1 hourafter administration. Compound 1 Form I, II, III, XXXVIII, XXX, or XXXIis preferably administered with a glass of water (approximately 8ounces/240 mL).

In another embodiment, the once-daily tablet or capsule formulationcomprises:

Ingredient (% w/w) Compound 1 Form I, II, III, XXXVIII, 31.68 XXX, orXXXI Microcrystalline Cellulose 38.85 Lactose anhydrous 19.42Hydroxypropyl Cellulose 3.00 Croscarmellose Sodium 3.00 TotalIntra-granular 95.95 Silicon dioxide, Colloidal 0.30 CroscarmelloseSodium 3.00 Magnesium Stearate 0.75 Total 100.00

In another embodiment, the once-daily tablet or capsule formulationcomprises:

Ingredient (% w/w) Compound 1 Form I, II, III, XXXVIII, 25.0-33.3 XXX,or XXXI Microcrystalline Cellulose q.s Hydroxypropyl Cellulose 3Poloxamer 0-3 Croscarmellose Sodium 6.0 Colloidal Silicon Dioxide 0.5Magnesium Stearate 0.5-1.0 Total 100

In another embodiment, the once-daily tablet or capsule formulationcomprises:

Ingredient Theoretical Quantity (mg/unit dose) Compound 1 Form I, II,III, 100.0 XXXVIII, XXX, or XXXI Microcrystalline Cellulose PH-102 155.4Lactose Anhydrous 60M 77.7 Hydroxypropyl Cellulose, EXF 12.0Croscarmellose Sodium 24 Colloidal Silicon Dioxide 1.2 MagnesiumStearate (Non-Bovine) 3.0 Opadry Yellow 16.0 Total 416

In another embodiment, the once-daily tablet or capsule formulationcomprises:

Ingredient Function % w/w Compound 1 Form I, II, III, XXXVIII, XXX,Active 31.7 or XXXI Ingredient Microcrystalline Cellulose (AvicelPH-102) Filler 38.9 Lactose Anhydrous (60M) Filler 19.4 HydroxypropylCellulose (EXF) Binder 3.0 Croscarmellose Sodium (Ac-Di-Sol) Disenegrant6.0 Colloidal Silicon Dioxide, Glidant 0.3 Magnesium Stearate Lubricant0.75 Opadry Yellow Film Coating which includes: Film Coating 4.00 HPMC2910/Hypromellose 6 cp Titanium dioxide Triacetin Iron Oxide Yellow

Any of the tablet or capsule formulations provided above can be adjustedaccording to the dose of the crystalline solid form of compound 1desired. Thus, the amount of each of the formulation ingredients can beproportionally adjusted to provide a table formulation containingvarious amounts of Compound 1 Form I, II, III, XXXVIII, XXX, or XXXI asprovided in the previous paragraphs. In another embodiment, theformulations can contain 20, 40, 60, or 80 mg of Compound 1 Form I, II,III, XXXVIII, XXX, or XXXI.

Another aspect of this disclosure relates to a method of treating cancercomprising administering to a subject in need thereof at least one ofsolid form of Compound 1 as described herein in any of the aspectsand/or embodiments, or combinations thereof. Methods of treatmentcomprising administering Compound 1 have been disclosed in, for example,commonly assigned PCT Patent Publication Nos. WO 2005/030140, WO 2011,017639, WO 2012/044572, WO 2012/044577, WO 2012/151326, WO 2013/043840,WO 2013/070890, WO 2013/070903, and WO2013/066296, and US PatentApplication Publication Nos. US 2012/0070368 and US 2012/0252840, eachof which is incorporated by reference herein in its entirety. The amountof the Compound 1 solid form or combinations thereof administered can bea therapeutically effective amount.

Another aspect of this disclosure relates to a method of treatingdiseases or disorders associated with uncontrolled, abnormal, and/orunwanted cellular activities associated with RTK overexpression,particularly cMET of RET overexpression, comprising administering to asubject in need of such treatment a therapeutically effective amount ofat least one solid form of Compound 1 as described herein in any of theaspects and/or embodiments, or combinations thereof, such as discussedabove.

Another aspect of this disclosure relates to a use of solid Compound 1according to any of the above embodiments for the manufacture of amedicament for the treatment of a disease or disorder discussed above.When dissolved, a solid or amorphous form according to this disclosureloses its solid state structure, and is therefore referred to as asolution of, for example, Compound 1. At least one solid form disclosedherein may be used to prepare at least one liquid formulation in whichat least one solid form according to the disclosure is dissolved and/orsuspended.

In another aspect, the invention is directed to a method of treatingcancer, comprising: administering a pharmaceutical dosage formcomprising Compound 1 Form I, II, III, XXXVIII, XXX, or XXXI or apharmaceutical composition comprising Compound 1 Form I, II, III,XXXVIII, XXX, or XXXI and a pharmaceutically acceptable carrier.

In one embodiment of this aspect, the invention is directed to a methodof treating cancer, comprising administering to a patient in need ofsuch treatment a pharmaceutical dosage form comprising 140 mg, 120 mg,100 mg, 80 mg, 60 mg, 40 mg, or 20 mg of Compound 1 Form I, II, III,XXXVIII, XXX, or XXXI or a pharmaceutical composition comprisingCompound 1 Form I, II, III, XXXVIII, XXX, or XXXI and a pharmaceuticallyacceptable carrier. In some embodiments, the dosage form is administeredorally with fasting orally once daily as a tablet or capsule. In someembodiments, Compound 1 Form I, II, III, XXXVIII, XXX, or XXXI or apharmaceutical composition comprising Compound 1 Form I, II, III,XXXVIII, XXX, or XXXI is administered as a tablet. In other embodiments,Compound 1 Form I, II, III, XXXVIII, XXX, or XXXI or a pharmaceuticalcomposition comprising Compound 1 Form I, II, III, XXXVIII, XXX, or XXXIis administered as a capsule.

Any of the tablet or capsule formulations provided above can be adjustedaccording to the dose of compound 1 desired. Thus, the amount of each ofthe formulation ingredients can be proportionally adjusted to provide atable formulation containing various amounts of compound 1 as providedin the previous paragraphs. In another embodiment, the formulations cancontain 20, 40, 60, or 80 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI.

In this method, the desired dosage of Compound 1 crystalline solid formcan be achieved using a combination of tablets or capsules as needed.For example to achieve a target dose of 20 mg would requireadministration of one 20 mg tablet or capsule. To achieve a target doseof 100 mg would require administration of one 80 mg tablet or capsuleand one 20 mg tablet or capsule. To achieve a target dose of 80 mg wouldrequire administration of one 80 mg tablet or capsule. To achieve atarget dose of 60 mg would require administration of three 20 mg tabletsor capsules.

In another embodiment of this method, 60 mg of compound 1 isadministered once daily to a patient with cancer in need of treatment.To achieve a dose of 60 mg of compound 1, a patient is administeredthree 20 mg tablets. The three 20 mg tablets can be taken at the sametime or sequentially. In a further embodiment, compound 1 is orallyadministered with fasting (that is, without eating) for approximatelytwo hours before and 1 hour after administration. Compound 1 ispreferably administered with a glass of water (approximately 8ounces/240 mL).

In another embodiment of this method, 40 mg of compound 1 isadministered once daily to a patient with cancer in need of treatment.To achieve a dose of 40 mg of compound 1, a patient is administered two20 mg tablets. The two 20 mg tablets can be taken at the same time orsequentially. In a further embodiment, compound 11 as one of thecrystalline solid forms disclosed herein (that is, Compound 1 Forms I,III, XXXVIII, XXX, or XXXI) is orally administered with fasting (thatis, without eating) for approximately two hours before and 1 hour afteradministration. Compound 1 is preferably administered with a glass ofwater (approximately 8 ounces/240 mL).

In another embodiment of this method, 20 mg of compound 1 isadministered once daily to a patient with cancer in need of treatment.To achieve a dose of 20 mg of compound 1, a patient is administered one20 mg tablet. In a further embodiment, compound 1 is orally administeredwith fasting (that is, without eating) for approximately two hoursbefore and 1 hour after administration. Compound 1 is preferablyadministered with a glass of water (approximately 8 ounces/240 mL).

In another embodiment, the method comprises administering Compound 1Form I, II, III, XXXVIII, XXX, or XXXI orally once daily as a tablet orcapsule as provided in the following table.

Ingredient (% w/w) Compound 1 Form I, II, III, XXXVIII, 31.68 XXX, orXXXI Microcrystalline Cellulose 38.85 Lactose anhydrous 19.42Hydroxypropyl Cellulose 3.00 Croscarmellose Sodium 3.00 TotalIntra-granular 95.95 Silicon dioxide, Colloidal 0.30 CroscarmelloseSodium 3.00 Magnesium Stearate 0.75 Total 100.00

In some embodiments, the pharmaceutical dosage form is administered as atablet. In other embodiments, the pharmaceutical dosage form isadministered as a capsule.

In another embodiment, the method comprises administering compound 1orally as one of the crystalline solid forms disclosed herein (that is,Compound 1 Forms I, II, III, XXXVIII, XXX, or XXXI) orally once daily asa tablet or capsule as provided in the following table.

Ingredient (% w/w) Compound 1 Form I, II, III, XXXVIII, 25.0-33.3 XXX,or XXXI Microcrystalline Cellulose q.s Hydroxypropyl Cellulose 3Poloxamer 0-3 Croscarmellose Sodium 6.0 Colloidal Silicon Dioxide 0.5Magnesium Stearate 0.5-1.0 Total 100In some embodiments, the pharmaceutical dosage form is administered as atablet. In other embodiments, the pharmaceutical dosage form isadministered as a capsule.

In another embodiment, the method comprises administering compound 1orally as one of the crystalline solid forms disclosed herein (that is,Compound 1 Forms I, II, III, XXXVIII, XXX, or XXXI) orally once daily asa tablet or capsule as provided in the following table.

Ingredient Theoretical Quantity (mg/unit dose) Compound 1 Form I, II,III, 100.0 XXXVIII, XXX, or XXXI Microcrystalline Cellulose PH-102 155.4Lactose Anhydrous 60M 77.7 Hydroxypropyl Cellulose, EXF 12.0Croscarmellose Sodium 24 Colloidal Silicon Dioxide 1.2 MagnesiumStearate (Non-Bovine) 3.0 Opadry Yellow 16.0 Total 416

In some embodiments, the pharmaceutical dosage form is administered as atablet. In other embodiments, the pharmaceutical dosage form isadministered as a capsule.

In another embodiment, the method comprises administering Compound 1Form I, II, III, XXXVIII, XXX, or XXXI orally once daily as a tablet orcapsule as provided in the following table.

Ingredient Function % w/w Compound 1 Form I, II, III, XXXVIII, XXX,Active 31.7 or XXXI Ingredient Microcrystalline Cellulose (AvicelPH-102) Filler 38.9 Lactose Anhydrous (60M) Filler 19.4 HydroxypropylCellulose (EXF) Binder 3.0 Croscarmellose Sodium (Ac-Di-Sol) Disenegrant6.0 Colloidal Silicon Dioxide, Glidant 0.3 Magnesium Stearate Lubricant0.75 Opadry Yellow Film Coating which includes: Film Coating 4.00 HPMC2910 /Hypromellose 6 cp Titanium dioxide Triacetin Iron Oxide YellowIn some embodiments, the pharmaceutical dosage form is administered as atablet. In other embodiments, the pharmaceutical dosage form isadministered as a capsule.

In some embodiments, the cancer to be treated is thyroid cancer, livercancer, gastrointestinal cancer, pancreatic cancer, bone cancer,hematologic cancer, skin cancer, kidney cancer, breast cancer, coloncancer, fallopian tube cancer, ovarian cancer, brain cancer, lung canceror prostate cancer.

In one embodiment, the cancer is thyroid cancer.

More particularly, the thyroid cancer is medullary thyroid cancer.

In one embodiment, the cancer in liver cancer.

More particularly, the liver cancer is hepatocellular carcinoma,cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, or hemagioma.

In one embodiment, the cancer is gastrointestinal cancer.

More particularly, the gastrointestinal cancer is cancer of theesophagous which is squamous cell carcinoma, adenocarcinoma, orleiomyosarcoma; cancer of the stomach which is carcinoma, or lymphoma;cancer of the pancreas, which is ductal adenocarcinoma, insulinoma,gucagonoma, gastrinoma, carcinoid tumors, or vipoma; cancer of the smallbowel, which is adenocarcinoma, lymphoma, carcinoid tumors, Karposi'ssarcoma, leiomyoma, hemagioma, lipoma; or cancer of the large bowel,which is adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, orleiomyoma.

In one embodiment, the cancer is cancer of the pancreas.

More particularly, the cancer of the pancreas is ductal adenocarcinoma,insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma.

In one embodiment, the cancer is bone cancer.

More particularly, the bone cancer is osteosarcoma, fibrosarcoma,malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma,malignant reticulum cell sarcoma, malignant giant cell tumor chordoma,osteocartiliginous exostoses, chondroblastoma, chondromyofibroma, orosteoid osteoma.

In one embodiment, the cancer is hematologic cancer.

More particularly, the hematologic cancer is myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, or myelodysplastic syndrome.

In one embodiment, the cancer is skin cancer.

More particularly, the skin cancer is malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, or Karposi's sarcoma.

In one embodiment, the cancer is renal cancer.

More particularly, the renal cancer is a renal tumor.

In one embodiment, the cancer is breast cancer.

More particularly, the breast cancer is a breast tumor.

In one embodiment, the cancer is colon cancer.

More particularly, the colon cancer is a colon cancer tumor.

In one embodiment, the cancer is fallopian tube cancer.

More particularly, the fallopian tube cancer is fallopian tubecarcinoma.

In one embodiment, the cancer is ovarian cancer.

More particularly, the ovarian cancer is ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, or melanoma.

In another embodiment, the cancer is prostate cancer.

More particularly, the prostate cancer is adenocarcinoma or sarcoma.

In another embodiment, the prostate cancer is castration resistantprostate cancer (CRPC).

In another embodiment, the cancer is lung cancer.

More particularly, the lung cancer is bronchogenic carcinoma (squamouscell, undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hanlartoma, or inesothelioma.

The antitumor effect of the dosage form of the invention is measuredusing serological and/or radiographic methods available to the skilledpractitioner. For serological methods, the relative concentration of acancer biomarker is measured before and after administration of Compound1 Form I, II, III, XXXVIII, XXX, or XXXI. A positive response means thatthere is a lower serological concentration of the biomarker aftertreatment as compared to the concentration before treatment. As anexample, for patients being treated for prostate cancer, particularlycastration-resistant prostate cancer, the serological concentration ofthe biomarker PSA will be determined before, during, and aftertreatment. Patients can be assigned a PSA response according to thefollowing criteria:

-   -   Complete Serological Response: PSA level less than 0.2 ng/mL        measured for 2 consecutive measurements at least 4 weeks apart.    -   Serological Partial Response (PR): decline of PSA value,        referenced to the pre-study level, by greater than or equal to        50% for 2 consecutive measurements at least 2 weeks apart.    -   PSA Stable Disease: Patients who do not meet the criteria for        response (CR or PR) or serological progression    -   Serological Progression (PD): is observed when the PSA        demonstrates an increase that is more than 50% of nadir, taking        as reference the lowest recorded PSA level since starting        therapy. Two consecutive increases must be documented with each        measurement obtained at least 2 weeks apart. On occasions, there        may be an intermediate fluctuant value. In accordance with the        Recommendations of the Prostate Cancer Clinical Trials Working        Group this will not restart the evaluation period so long as the        intermediate value was not below the previous nadir[18]. The        date of first recorded increase (not defeated by a subsequent        drop in PSA level to create a new nadir) will be deemed the date        of progression. If a patient achieves a PSA that is less than 2        ng/mL, progression will only be deemed to have been confirmed        once: (1) There has been an observed rise that is more than 50%        of nadir since starting ADT; AND (2) The confirming increase was        to a value that is more than 2.0 ng/mL (the unconfirmed and        second increase may be a value that is less than 2.0 ng/mL but        greater than 50% of nadir since starting ADT).

These serological response levels can be modified as needed based on thebiomarker at issue.

In one embodiment, a complete serological response is observed inpatients being treated with the dosage form. In another embodiment, aserological partial response is observed in patients being treated withthe dosage form. In a further embodiment, stable disease is observed inpatients being treated with the dosage form.

With respect to radiographic methods, radiographic disease progressionis defined by RECIST 1.1 for soft tissue disease, or the appearance oftwo or more new bone lesions on bone scan. Progression in the absence ofclear symptomatic worsening at the first scheduled reassessment aftercommencement of treatment requires a confirmatory scan at later point intime. Standard imaging procedures available to the skilled practitioner,including technetium bone scans and CT scans can be used to measureradiographic effect. Other radiographic methods such as NaF and FDG-PETmay also be used to measure radiographic effect.

As indicated previously, the amount of Compound 1 Form I, II, III,XXXVIII, XXX, or XXXI that is administered can be adjusted to avoidadverse events. For example, in one embodiment, a pharmaceutical dosagecomprising 60 mg of Compound 1 Form I, II, III, XXXVIII, XXX, or XXXI isadministered to a patient that had one or more adverse events at adosage greater than 60 mg.

In another embodiments, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a pharmaceutical dosage between 80 mg and 160 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 70 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 80 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevent at a dosage of 90 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 100 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 120 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 130 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 140 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 150 mg.

In another embodiment, 60 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 160 mg.

In other embodiments, 60 mg of Compound 1 Form I, II, III, XXXVIII, XXX,or XXXI is administered to a patient that had one or more adverse eventsat a pharmaceutical dosage of 140 mg or 100 mg.

In another embodiment, the pharmaceutical dosage comprising 40 mg ofCompound 1 Form I, II, III, XXXVIII, XXX, or XXXI is administered to apatient that had one or more adverse events at a dosage greater than 40mg.

In another, 40 mg of Compound 1 Form I, II, III, XXXVIII, XXX, or XXXIis administered to a patient that had one or more adverse events at apharmaceutical dosage between 60 mg and 160 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 50 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 60 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 70 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 80 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 90 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 100 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 120 mg of compound 1.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 130 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 140 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 150 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 160 mg.

In another embodiment, 40 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a pharmaceutical dosage of 140 mg, 100 mg, or 60 mg.

In another embodiment, the pharmaceutical dosage comprising 20 mg ofCompound 1 Form I, II, III, XXXVIII, XXX, or XXXI is administered to apatient that had one or more adverse events at a dosage greater than 60mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a pharmaceutical dosage between 40 mg and 160 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 30 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 40 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 50 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 60 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 70 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 80 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 90 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 100 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 120 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 130 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 140 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 150 mg.

In another embodiment, 20 mg of Compound 1 Form I, II, III, XXXVIII,XXX, or XXXI is administered to a patient that had one or more adverseevents at a dosage of 160 mg.

In other embodiments, 20 mg of Compound 1 Form I, II, III, XXXVIII, XXX,or XXXI is administered to a patient that had one or more adverse eventsat a pharmaceutical dosage of 140 mg, 100 mg, 60 mg, or 40 mg.

In some embodiments, the adverse event is one or more of diarrhea,stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreasedweight, decreased appetite, nausea, fatigue, oral pain, hair colorchanges, dysgeusia, hypertension, abdominal pain, constipation,increased AST, increased ALT, lymphopenia, increased alkalinephosphatase, hypocalcemia, neutropenia, thrombocytopenia,hypophosphatemia, hyperbilirubinemia, perforations, fistulas,hemorrhage, thromboembolic events, wound complications, osteonecrosis ofthe jaw, proteinuria, reversible posterior leukoencephalopathy syndrome(RPLS), and embryo-fetal toxicity.

In some embodiments, the adverse event is Grade 1. In some embodiments,the adverse event is Grade 2. In some embodiments, the adverse event isGrade 3. In some embodiments, the adverse event is Grade 4. In someembodiments, the adverse event is Grade 5.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 4 adverse event. In another embodiment, upon resolution orimprovement of the Grade 4 adverse event, the dose of compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 4 adverse event means returning to baseline.In other embodiments, resolution or improvement of the Grade 4 adverseevent means resolution to a Grade 1 adverse event.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 3 adverse event. In another embodiment, upon resolution orimprovement of the Grade 3 adverse event, the dose of compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 3 adverse event means returning to baseline.In other embodiments, resolution or improvement of the Grade 4 adverseevent means resolution to a Grade 1 adverse event.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 2 adverse event. In another embodiment, upon resolution orimprovement of the Grade 2 adverse event, the dose of compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 2 adverse event means returning to baseline.In other embodiments, resolution or improvement of the Grade 2 adverseevent means resolution to a Grade 1 adverse event.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 1 adverse event. In another embodiment, upon resolution orimprovement of the Grade 4 adverse event, the dose of compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 1 adverse event means returning to baseline.

In some embodiments, the dose is further reduced one or more timesfollowing the first reduction as a result of one or more adverse events.In one embodiment, the dose is reduced a first time. In anotherembodiment, the dose is reduced a first and second time. In anotherembodiment, the dose is reduced a first, second, and third time.

General Preparation Methods of Crystalline Solid Forms

Crystalline solid forms may be prepared by a variety of methodsincluding, but not limited to, for example, crystallization orrecrystallization from a suitable solvent mixture; sublimation; growthfrom a melt; solid state transformation from another phase;crystallization from a supercritical fluid; and jet spraying. Techniquesfor crystallization or recrystallization of crystalline solid forms of asolvent mixture include, but are not limited to, for example,evaporation of the solvent; decreasing the temperature of the solventmixture; crystal seeding of a supersaturated solvent mixture of thecompound and/or salt thereof; crystal seeding a supersaturated solventmixture of the compound and/or a salt from thereof; freeze drying thesolvent mixture; and adding antisolvents (countersolvents) to thesolvent mixture. High throughput crystallization techniques may beemployed to prepare crystalline solid forms including polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, andcharacterization of drug crystals, are discussed in Solid-StateChemistry of Drugs, S. R. Bym, R. R. Pfeiffer, and J. G. Stowell, 2^(nd)Edition, SSCI, West Lafayette, Ind. (1999).

In a crystallization technique in which solvent is employed, thesolvent(s) are typically chosen based on one or more factors including,but not limited to, for example, solubility of the compound;crystallization technique utilized; and vapor pressure of the solvent.Combinations of solvents may be employed. For example, the compound maybe solubilized in a first solvent to afford a solution to whichantisolvent is then added to decrease the solubility of the Compound 1in the solution and precipitate the formation of crystals. Anantisolvent is a solvent in which a compound has low solubility.

In one method that can be used in preparing crystals, Compound 1 can besuspended and/or stirred in a suitable solvent to afford a slurry, whichmay be heated to promote dissolution. The term “slurry,” as used herein,means a saturated solution of the compound, wherein such solution maycontain an additional amount of compound to afford a heterogeneousmixture of compound and solvent at a given temperature.

Seed crystals may be added to any crystallization mixture to promotecrystallization. Seeding may be employed to control growth of aparticular polymorph and/or to control the particle size distribution ofthe solid product. Accordingly, calculation of the amount of seedsneeded depends on the size of the seed available and the desired size ofan average product particle as described, for example, in ProgrammedCooling Batch Crystallizers,” J. W. Mullin and J. Nyvlt, ChemicalEngineering Science, 1971, 26, 3690377. In general, seeds of small sizeare needed to effectively control the growth of crystals in the batch.Seeds of small size may be generated by sieving, milling, or micronizinglarge crystals, or by microcrystallizing a solution. In the milling ormicronizing of crystals, care should be taken to avoid changingcrystallinity from the desired solid form (i.e., changing to anamorphous or other polymorphic form).

A cooled crystallization mixture may be filtered under vacuum and theisolated solid product washed with a suitable solvent, such as, forexample, cold recrystallization solvent. After being washed, the productmay be dried under a nitrogen purge to afford the desired solid form.The product may be analyzed by a suitable spectroscopic or analyticaltechnique including, but not limited to, for example, differentialscanning calorimetry (DSC); x-ray powder diffraction (XRPD); andthermogravimetric analysis (TGA) to assure the solid form of thecompound has been formed. The resulting solid form may be produced in anamount greater than about 70 weight percent isolated yield, based on theweight of the compound originally employed in the crystallizationprocedure, and preferably greater than about 90 weight percent isolatedyield. Optionally, the product may be delumped by being comilled orpassed through mesh screen.

The features and advantages of this disclosure may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of thisdisclosure that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. The disclosure is further illustrated by the followingexamples, which are not to be construed as limiting the disclosure inscope or spirit to the specific procedures described in them.

Synthesis

The solid compounds of the invention can be synthesized from readilyavailable starting materials as described below and in the Examples. Itwill be appreciated that while specific process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Generally, the reactions are conducted in asuitable inert diluent, examples of which include, but are not limitedto, methanol, ethanol, isopropanol, isobutanol, ethyl acetate,acetonitrile, dichloromethane, methyl t-butyl ether, and the like, andmixtures thereof, typically containing water. Upon completion of any ofthe foregoing reactions, the solid compounds can be isolated from thereaction mixture by any conventional means such as precipitation,concentration, centrifugation, and the like.

The Compound 1 employed in the invention can be readily prepared fromcommercially available starting materials and reagents using theprocedures described in the Examples, or using the procedures describedin WO 2005/030140, as well as in WO 2012/109510 and WO 2013/059788, eachof which is incorporated by reference in its entirety.

The molar ratios described in the methods of the invention can bereadily determined by various methods available to those skilled in theart. For example, such molar ratios can be readily determined by ¹H NMR.Alternatively, elemental analysis and HPLC methods can be used todetermine the molar ratio.

Examples

The following examples illustrate the scope of the invention. Theexamples and preparations which follow are provided to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Experimental Techniques X-Ray Powder Diffraction (XRPD)

XRPD analyses were performed using a Panalytical Xpert Prodiffractometer equipped with a Cu X-ray tube and a Pixcel detectorsystem. The isothermal samples were analyzed in transmission mode andheld between low density polyethylene films. The XRPD analysis programused an analysis range of 3-40°2θ, step size 0.013°, counting time 99seconds, and an approximate run time of 22 minutes. Variable temperaturesamples were loaded into capillaries and temperature controlled using anOxford Cryostream system. XRPD patterns were sorted, manipulated, andindexed using HighScore Plus 2.2c software.

Differential Scanning Calorimetry (DSC)

DSC analyses were carried out on a Perkin Elmer Jade DifferentialScanning Calorimeter. Accurately weighed samples were placed in crimpedaluminum pans. Each sample was heated under nitrogen at a rate of 10°C./minute to a maximum of 300° C. Indium metal was used as thecalibration standard. Temperatures were reported at the transition onsetto the nearest 0.01 degree.

Hyper Differential Scanning Calorimetry (DSC)

Hyper DSC analyses were carried out on a Perkin Elmer DiamondDifferential Scanning Calorimeter. Accurately weighed samples wereplaced in crimped aluminum pans. Each sample was heated and cooled underhelium over two cycles at a rate of 300° C./minute using a temperaturerange of −50 to 300° C. Indium metal was used as the calibrationstandard.

Hyper DSC allows the measurement of thermal events using very fastscanning rates. The fast scanning rate results in a much increased heatflow signal and therefore greatly increases sensitivity. This allowsextremely low energy transitions, such as the glass transitiontemperature (Tg), to be identified and measured much more effectively.

Thermogravimetric Differential Thermal Analysis (TG/DTA)

Thermogravimetric analyses were carried out on a Mettler Toledo TGA/DSC1STARe. The calibration standard was indium. Samples were placed in analuminum sample pan, inserted into the TG furnace and accuratelyweighed. The heat flow signal was stabilized for one minute at 30° C.,prior to heating to a maximum of 300° C. in a stream of nitrogen at arate of 10° C./minute.

¹H/¹³C Nuclear Magnetic Resonance Spectroscopy (NMR)

NMR analysis was carried out on either a Bruker 400 MHz or 500 MHzinstrument in DMSO-d6.

Optical and Hot-Stage Microscopy

Microscopy analysis was carried out on an Olympus BX51 microscope.Photomicrographs of cabozantinib were obtained at objective lensmagnifications ×10 using a polarized light source. Hot stage microscopyanalyses were performed using a Linkam hot stage accessory. Solidsamples were heated using pre-set temperature programs which includedthe selected ramp rate, final temperature, and interval hold times ifrequired for individual samples.

Dynamic Vapor Sorption (DVS)

Dynamic Vapor Sorption (DVS) was performed using a Hiden AnalyticalInstruments IGAsorp Vapor Sorption Balance. Approximately 30 mg ofsample was placed into a wire-mesh Vapor sorption balance pan, loadedinto the IGAsorp Vapor sorption balance and held at 25° C.+0.1° C. Thesample was subjected to a step profile from 0 to 90% RH at 10%increments, followed by desorption from 80% RH to 0% RH at 10%increments. The equilibrium criterion was set to 99.0% step completionwithin a minimum of 60 minutes and a maximum of 5 hours for eachincrement. The weight change during the sorption cycle was monitored,allowing for the hygroscopic nature of the sample to be determined. Thedata collection interval was in seconds.

Fourier Transfer Infra-Red (FTIR) Spectroscopy

Fourier Transform Infra-Red (FTIR) was performed using Attenuated TotalReflectance (ATR) on a Thermonicolet 370 Avatar Infra-Red Spectrometerequipped with an ATR Smart Golden Gate Accessory. A small portion of thesample was placed on the ATR crystal. The sample spectrum was collectedin % Transmittance in the range of 650 cm⁻¹-4000 cm⁻¹, using aresolution of 4 cm⁻¹ and an acquisition of 20 scans.

EXPERIMENTS Preparation of Forms

Preparation of Compound 1 Form I

Compound 1 Form I was prepared by adding Compound 1 Form I (1 g) oramorphous material and THF (12 mL) to a flask and agitating at ambienttemperature until dissolved. Water (about 20 mL) was added to theambient temperature solution over approximately 2 hours, stirred forabout 8 hours, and the solids were collected and dried. The material wasfully characterized.

Preparation of Compound 1 Form II

Compound 1 Form I (1 g) and THF (12 mL) were added to a flask andagitated at ambient temperature until dissolved. Water (about 12 mL) wasadded to the ambient temperature solution over approximately 2 hours,stirred for about 8 hours, and the solids were collected and dried. Thematerial was fully characterized.

Preparation of Compound 1 Form III

Compound 1 Form I (1 g) and THF (12 mL) were added to a flask andagitated at ambient temperature until dissolved. The contents of theflask were heated at a temperature from 30 to 50° C. and the pressurereduced to approximately 100 torr. After approximately one-half of thevolume was removed by distillation, methanol was added to the flask toachieve the approximate starting volume. This distillation was repeatedat least two times, and the contents of the flask returned to ambienttemperature and pressure. The resulting solids were collected, dried,and fully characterized.

Preparation of Compound 1 Form XXVIII

Compound 1 Form I (150 mg) and 1-butanol (1 mL) were added to a vial andstirred at 5° C. for 7 days. The solids were recovered by filtration,air dried, and characterized. In another scale-up method, amorphousCompound 1 was slurried in nitromethane for 11 days, and the solids werecollected, dried, and desolvated on a TG/DTA at 110° C.+30° C. for 15minutes. The resulting solids were fully characterized.

Preparation of Compound 1 Form XXX

Amorphous Compound 1 (approximately 100 mg) was added to a vial whichwas placed unsealed inside a larger vial containing acetone. After 5days, the sample was desolvated on the TG/DTA at 105° C. for 25 minutes,followed by desolvation at 100° C.+30° C. for 40 minutes to yieldpattern XXX material. The material was fully characterized.

Preparation of Compound 1 Form XXXI

Compound 1 Form III (140 mg) and EtOH:water (44:56% v/v, 5.6 mL) werestirred in a sealed vial for 3 hours to allow for saturation. Compound 1Form I (50 mg) and pattern XXXI cabozantinib (approximately 1-2 mg) wereadded, and the mixture was stirred for 3 days to allow for completeconversion to Compound 1 Form XXXI. The solid was recovered by vacuumfiltration and dried on the filter with vacuum suction for 30 minutesprior to analysis by XRPD.

Synthesis of Amorphous Compound 1

Hyper DSC was performed in order to generate amorphous material fromfast cooling of molten forms of Compound 1.

Amorphous Compound 1 was generated by melting Compound 1 followed byfast cooling. A thermogram taken from the second heating of aheat-cool-heat cycle demonstrates the presence of a Tg, observed at99.19° C. (half-height value).

Amorphous Compound 1 was generated by melting Compound 1 Form IIfollowed by fast cooling. A thermogram taken from the second heating ofa heat-cool-heat cycle demonstrates the presence of a Tg, observed at103.72° C. (half-height value).

Amorphous Compound 1 was generated by melting Compound 1 Form IIIfollowed by fast cooling. An expanded thermogram taken from the secondheating of a heat-cool-heat cycle demonstrated the presence of a Tg,observed at 120.72° C. (half-height value), higher than was observedwith Compound 1 Forms I or II, because in these forms, the solvent vaporgenerated plasticizes the amorphous state and lowers the Tg.

Amorphous Compound 1 was also generated on a 200 mg scale from CompoundForm I, Compound 1 Form II, or Compound 1 Form III material byfreeze-drying a filtered solution in dioxane. Compound 1 (200 mg) wasdissolved in dioxane (20 mL), filtered through a 0.2 μm filter into around-bottomed flask containing liquid nitrogen. The flask was rotatedwithin a Dewar flask containing liquid nitrogen, forming frozen dropletsinside the flask. The flask was lyophilized under vacuum (0.08 mbar) for18 hours at 20° C. XRPD analysis displayed a halo pattern indicative ofX-ray amorphous material (FIG. 1).

Data for Crystalline Solid Forms

X-ray powder diffraction (XRPD) data (CuKα, (° 2θ+0.2°2θ) for Compound 1Forms I, II, III, XXVIII, XXX, and XXXI is summarized in Table 1.

TABLE 1 Compound 1 Form Form Form Form Form Form I II III XXVIII XXXXXXI 10.1 6.4 7.0 6.5 7.2 5.0 11.9 11.6 7.8 9.5 7.5 10.0 12.9 12.1 9.411.8 10.0 11.9 14.4 12.6 11.1 12.3 12.0 13.0 16.0 12.9 12.6 13.0 12.414.4 23.0 14.8 14.1 15.5 13.5 16.1 24.7 14.9 15.5 16.9 15.8 19.9 18.017.3 17.7 19.8 21.4 18.8 22.3 19.1 23.8 20.2 24.3 21.7 22.3

Compound 1 Form I

The XRPD pattern obtained for Compound 1 Form is shown in FIG. 2.Thermogravimetric/Differential Thermal Analysis (TG/DTA) was performedto determine the thermal profile and associated % weight changes ofCompound 1 Form I. As depicted in FIG. 3, weight loss of approximately6.5% from 25-80° C. was noted, which corresponds to approximately 1.92moles of water and confirms that Compound 1 Form I cabozantinib is adihydrate. A second weight loss at temperatures greater than 200° C.corresponds to the initiation of decomposition of the material. Twoendotherms were observed at onset temperature approximately 56.6° C. and116.7° C. These correspond to the loss of water and subsequent meltingof the dehydrated form respectively.

The DSC thermogram obtained for Compound 1 Form I at 10° C./min is shownin FIG. 4. The thermogram showed two endotherms, the first one at onset68.13° C. due to loss of water, and the second endotherm at onset112.70° C., which is the melting endotherm. This was confirmed visuallyby hot-stage microscopy.

The FT-IR spectrum obtained for the material is shown in FIG. 5 andincludes stretches at 3445, 3200, 1671, 1561, 1508, 1433, 1431, 1353,1254, 1223, 826 FTIR (cm⁻¹). The spectrum was shown to conform to thematerial structure with all expected functional groups present. Thepresence of water is clearly visible (broad, 3200 cm⁻¹), and peak shiftsare significantly different to anhydrous Compound 1 Form III. ¹H NMR(FIG. 6) conformed to structure.

Compound 1 Form II

The XRPD pattern obtained for Compound 1 Form II is shown in FIG. 7 andis indicative of a highly crystalline material.Thermogravimetric/Differential Thermal Analysis (TG/DTA) was performedto determine the thermal profile and associated % weight changes (FIG.8).

Weight loss of approximately 9.8% was observed, and this was attributedto loss of a mixture of THF and water. A second weight loss attemperatures above 140° C. may be due to a mixture solvent loss anddecomposition. The first endotherm, at onset 62.7° C., corresponds tothe loss of solvent and/or water. The second at onset approximately196.5° C. corresponds to the melt of an anhydrous form, later confirmedas low crystallinity Compound 1 Form III (see below).

The DSC thermogram (FIG. 9) showed two endotherms, the first at onset71.47° C. was a broad peak corresponding to loss of solvent/water. Anexotherm was observed at onset approximately 119.8° C., which suggestsrecrystallization to another form. A second endotherm was noted at onset206.83° C., which corresponds to the melting point of Compound 1 FormIII.

¹H NMR (FIG. 10) of Compound 1 Form II conforms to structure and showsthe presence of THF (0.4 mole equivalents). This implies that 5.5% w/wof weight loss from TGA can be attributed to THF and the remainder towater (4.3% w/w, or approximately 1.2 mol eq).

Compound 1 Form III

The XRPD pattern for Compound 1 Form III is shown in FIG. 11 and isindicative of a highly crystalline material.Thermogravimetric/Differential Thermal Analysis (TG/DTA) was performedto determine the thermal profile and associated % weight changes ofCompound 1 Form III (FIG. 12).

No weight loss was observed below 200° C., suggesting as Compound 1 FormIII is an anhydrous material. A melting endotherm was observed at onsettemperature 220.37° C. Weight loss due to decomposition was alsoobserved above this point. The DSC thermogram obtained for Compound 1Form III (FIG. 13) confirmed the melting onset at 220.59° C. Hot stagemicroscopy showed the onset of melting between 220° C. and 230° C., withthe material completely molten by 235° C.

¹H NMR (DMSO-d6, FIG. 15) conformed to structure and showed an absenceof solvent. The FT-IR spectrum obtained for the material is shown inFIG. 14 and was shown to conform to the material structure with allexpected functional groups present. FTIR (cm⁻¹): 3240, 3061, 1639, 1560,1504, 1480, 1430, 1213, 1165, 850, 822.

Compound 1 Form XXVIII

The XRPD for Compound 1 Form XXVIII is shown in FIG. 16. The intensenarrow peaks are indicative of a highly crystalline material. Polarizedlight microscopy showed birefringent crystals with particle sizegenerally less than 10 μm.

TG/DTA (FIG. 17) showed no weight loss from 25° C. to 180° C.,confirming that the material was an anhydrous form. DSC (FIG. 18) showedan initial endothermic event at onset 190.62° C., a recrystallizationexotherm at onset 193.65° C. and another endotherm at onset 205.83° C.These results indicate that Compound 1 Form XXVIII melts andrecrystallizes to Compound 1 Form III which subsequently melts. Themelting onset is lower than that observed for pure Compound 1 Form III(onset 220.59° C.), most likely due to lower crystallinity.

Hyper DSC was performed in order to generate amorphous material fromfast cooling of molten Compound 1 Form XXVIII and determine thetemperature of glass transition (Tg) during the reheat cycle. Thethermogram demonstrates the presence of a Tg, observed during the secondheating of a heat-cool-heat cycle at 120.85° C. (half-height value). TheTg is consistent with Compound 1 Form XXVIII being an anhydrous Form, asit is similar to the Tg of Compound 1 Form III material.

¹H NMR (FIG. 20) of Compound 1 Form XXVIII showed the material toconform to structure and contain no solvent. Infra-red spectroscopycarried out on Compound 1 Form XXVIII (FIG. 19) was broadly similar toCompound 1 Form III, except in the 1700-1500 cm⁻¹ region. Typicallyassociated with carbonyl stretching, this implies differences in thehydrogen bonding network. FTIR (cm⁻¹): 3038, 1686, 1531, 1504, 1480,1350, 1213, 994, 856, 831.

Compound 1 Form XXX

The XRPD pattern for Compound 1 Form XXX, shown in FIG. 21, isindicative of a crystalline material. Polarized light microscopyconfirms that the material is crystalline with some aggregation oragglomeration present.

Thermal analysis (TG/DTA) (FIG. 22) did not show significant weight lossand confirmed Compound 1 Form XXX was an anhydrous form. The onset ofmelting (117.9° C.) was slightly higher than that observed by DSC (FIG.23), which showed an initial melt at onset 110.6° C., followed by arecrystallization event to Compound 1 Form III at onset 136.25° C. and afinal melt at onset 205.64° C. As was the case for otherrecrystallization events, the Compound 1 Form III had a lower onsettemperature as a result of lower crystallinity.

¹H NMR (FIG. 25) of Compound 1 Form XXX showed the material to conformto structure and contain ˜1.1% w/w (0.1 mol eq) of residual acetone.Several attempts to reduce this solvent level using heat, vacuum drying,and humid drying were unsuccessful and suggested that some acetoneremains trapped within the crystal structure. Infra-red spectroscopy(FIG. 24) differs from Compound 1 Form III and Compound 1 Form XXVIII inthe carbonyl stretch region. The residual acetone carbonyl can be seenat 1717 cm−1, which is comparable to liquid acetone (1715 cm−1) andimplies that the acetone is not hydrogen bonded within the crystalstructure in Compound 1 Form XXX. FTIR (cm⁻¹): 3250, 1652, 1504, 1480,1432, 1349, 1211, 1197, 995, 850, 821.

Compound 1 Form XXXI

The XRPD of Compound 1 Form XXXI (FIG. 26) is indicative of crystallinematerial. Thermal analysis (TG/DTA) (FIG. 27) showed two endothermicevents; the first at onset 72.7° C. with an associated weight loss of6.61% (1.97 mol equiv of water) was due to dehydration and indicatesthat Compound 1 Form XXXI is a dihydrate.

The hygroscopicity and the sorption properties of Compound 1 Form XXXIwere determined using Dynamic Vapor Sorption (DVS). The program differedfrom that used for Compound 1 Form I in that the sample was dried at 0%RH prior to performing sorption and desorption. The isotherm showed thematerial lost −7% weight on drying to 0% RH, consistent with loss of 2mol eq of water.

The DSC thermogram (FIG. 28) obtained for Compound 1 Form XXXI wascomplex and showed three endothermic events occurring between −67° C.and −130° C.

¹H NMR (FIG. 30) of Compound 1 Form Compound 1 XXXI showed the materialto conform to structure. Infra-red spectroscopy (FIG. 29) conformed tothe spectrum of Compound 1 Form I (FIG. 5) within experimental error.FTIR (cm⁻¹): 3444, 3251, 1672, 1530, 1507, 1483, 1430, 1354, 1256, 1223,1148, 1000, 856, 843, 826.

Compound 1 Amorphous Form

The XRPD for Compound 1 Amorphous Form is shown in FIG. 1. Thehygroscopicity and the sorption properties of Compound 1 Amorphous Formwere determined using Dynamic Vapor Sorption (DVS). The sample was driedat 0% RH prior to performing sorption and desorption. The isothermshowed the material exhibits slow uptake of moisture from 0% RH to 60%RH. The rate of uptake of moisture increased from 60% RH to 90% RH. Theisotherm showed the total weight gain observed between 0% RH and 80% RHto be 4% w/w which indicated that the sample was hygroscopic, accordingto the European Pharmacopoeia classification. The rate of desorption wasslower than the rate of sorption, as hysteresis was observed. All of themoisture adsorbed was lost upon return to 0% RH. XRPD of the sample postDVS confirmed that no crystallization had occurred (FIG. 1).

The physical stability of amorphous material was assessed under a rangeof stress conditions including temperature stress, relative humidity(RH), and exposure to selected organic vapors. Surprisingly, thematerial was stable to heat stressing at 100° C. for 4 days (i.e. belowTg of 120° C.). Exposure to relative humidity between 23% and 98% for7-10 days induced no crystallization. From DVS, a water uptake ofapproximately 5% was observed at 90% RH and thus the plasticizing effectof water can be estimated from the Fox equation. This suggests that theamorphous form should have a glass transition of approximately 87° C. at90% RH. A Tg over 100° C. coupled with the above stress data reveal thatamorphous Compound 1 contains an exceptional combination of favorablephysical attributes that provide utility in a variety of drug productformulations.

OTHER EMBODIMENTS

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive. The scope of the invention should, therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the following appended claims,along with the full scope of equivalents to which such claims areentitled.

1. A crystalline solid form of Compound 1:

wherein the crystalline solid form is selected from Compound 1 Form III,Compound 1 Form XXVIII, and Compound 1 Form XXX as depicted in FIG. 11,16, or 21 or a solvate crystalline solid form selected from Compound 1Form I and Compound 1 Form XXXI, as depicted in FIG. 2 or
 26. 2. Thecrystalline solid form of compound 1 claim 1 with an XRPD patternselected from the group consisting of: Compound 1 Form I Form III FormXXVIII Form XXX Form XXXI 10.1 7.0 6.5 7.2 5.0 11.9 7.8 9.5 7.5 10.012.9 9.4 11.8 10.0 11.9 14.4 11.1 12.3 12.0 13.0 16.0 12.6 13.0 12.414.4 23.0 14.1 15.5 13.5 16.1 23.6 15.5 16.9 15.8 19.9 24.7 17.3 17.719.8 21.4 22.3 19.1 23.8 24.3 21.7 22.3


3. The crystalline solid form of compound 1 of claims 1-2 with an XRPDpattern selected from the group consisting of: Compound 1 Form I FormIII Form XXVIII Form XXX Form XXXI 10.1 7.0 6.5 7.2 5.0 11.9 7.8 9.5 7.510.0 12.9 9.4 11.8 10.0 11.9 14.4 11.1 12.3 12.0 13.0 16.0 12.6 13.012.4 14.3 23.6 14.1 17.7 13.5 14.4 22.3 19.1 19.8 16.1 24.3 22.3 19.923.8


4. The crystalline solid form of compound 1 of claims 1-3 with an XRPDpattern selected from the group consisting of: Compound 1 Form I FormIII Form XXVIII Form XXX Form XXXI 11.9 7.0 6.5 7.2 14.4 14.4 7.8 12.37.5 16.1 16.0 11.1 17.7 13.5 19.9 23.6 14.1 19.1 19.8 23.8


5. The crystalline solid form of compound 1 of claims 1-4 with an XRPDpattern selected from the group consisting of: Compound 1 Form I FormIII Form XXVIII Form XXX Form XXXI 10.1 9.4 9.5 10.0 5.0 12.9 11.5 11.812.0 10.0 12.6 13.0 12.4 11.9 22.3 22.3 13.0 24.3 14.3


6. The crystalline solid form of compound 1 of claims 1-5 having an XRPDpatterns as represented by: Compound 1 Form I Form III Form XXVIII FormXXX Form XXXI FIG. 2 FIG. 11 FIG. 16 FIG. 21 FIG. 26


7. A pharmaceutical composition comprising a therapeutically effectivedose of a substantially pure crystalline solid form of compound 1 asrecited in claims 1-5 and a pharmaceutically acceptable carrier.
 8. Apharmaceutical composition comprising a therapeutically effective doseof a mixture of crystalline solid forms of compound 1 as recited inclaims 1-5 and a pharmaceutically acceptable carrier.
 9. A method oftreating cancer comprising administering to a subject a therapeuticallyeffective amount of a crystalline solid form of Compound 1 as recited inclaims 1-5.
 10. A method of treating cancer comprising administering toa subject a pharmaceutical composition as recited in claims 6 and
 7. 11.The method of claims 9-10, wherein the cancer is selected from thyroidcancer (including medullary thyroid cancer) stomach cancer, esophagealcarcinoma, kidney cancer (including renal carcinoma), liver cancer(including hepatocellular carcinoma), ovarian carcinoma, cervicalcarcinoma, large bowel cancer, small bowel cancer, brain cancer(including astrocytic tumor, which includes glioblastoma, giant cellglioblastoma, gliosarcoma, and glioblastoma with oligodendroglialcomponents), lung cancer (including non-small cell lung cancer), bonecancer, prostate carcinoma (including castration resistant prostatecancer), pancreatic carcinoma, skin cancer, bone cancer, lymphoma, solidtumors, Hodgkin's disease, or non-Hodgkin's lymphoma.
 12. A method oftreating diseases or disorders associated with uncontrolled, abnormal,and/or unwanted cellular activities due to cMET or RET overexpression,comprising administering to a subject in need of such treatment atherapeutically effective amount of at least one solid form of Compound1 as recited in claims 1-6.
 13. A method of treating diseases ordisorders associated with uncontrolled, abnormal, and/or unwantedcellular activities due to cMET or RET overexpression, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition comprising at least onesolid form of Compound 1 as recited in claims 1-6 and a pharmaceuticallyacceptable carrier.
 14. A process for preparing amorphous Compound 1:

comprising: freeze-drying a filtered solution of Compound 1 Form I,Compound 1 Form II, or Compound 1 Form III in dioxane.
 15. AmorphousCompound 1 prepared according to claim
 13. 16. A pharmaceuticalformulation, comprising: Ingredient (% w/w) Compound I Solid Form 1, II,III, 31.68 XXXVIII, XXX, OR XXXI Microcrystalline Cellulose 38.85Lactose anhydrous 19.42 Hydroxypropyl Cellulose 3.00 CroscarmelloseSodium 3.00 Total Intra-granular 95.95 Silicon dioxide, Colloidal 0.30Croscarmellose Sodium 3.00 Magnesium Stearate 0.75 Total 100.00


17. A pharmaceutical formulation, comprising: Ingredient (% w/w)Compound 1 Form I, II, III, XXXVIII, 25.0-33.3 XXX, or XXXIMicrocrystalline Cellulose q.s Hydroxypropyl Cellulose 3 Poloxamer 0-3Croscarmellose Sodium 6.0 Colloidal Silicon Dioxide 0.5 MagnesiumStearate 0.5-1.0 Total 100


18. A pharmaceutical formulation, comprising: Ingredient TheoreticalQuantity (mg/unit dose) Compound 1 Form I, II, III, 100.0 XXXVIII, XXX,or XXXI Microcrystalline Cellulose PH-102 155.4 Lactose Anhydrous 60M77.7 Hydroxypropyl Cellulose, EXF 12.0 Croscarmellose Sodium 24Colloidal Silicon Dioxide 1.2 Magnesium Stearate (Non-Bovine) 3.0 OpadryYellow 16.0 Total 416


19. A pharmaceutical formulation, comprising: Ingredient % w/w Compound1 Form I, II, III, XXXVIII, XXX, 31.7 or XXXI Microcrystalline Cellulose(Avicel PH-102) 38.9 Lactose Anhydrous (60M) 19.4 HydroxypropylCellulose (EXF) 3.0 Croscarmellose Sodium (Ac-Di-Sol) 6.0 ColloidalSilicon Dioxide, 0.3 Magnesium Stearate 0.75 Opadry Yellow Film Coatingwhich includes: 4.00 HPMC 2910/Hypromellose 6 cp Titanium dioxideTriacetin Iron Oxide Yellow